- Email: [email protected]
Primary Ewing Sarcoma of Lumbar Spine With Massive Intraspinal Extension
Primary Ewing Sarcoma of Lumbar Spine With Massive Intraspinal Extension Xianyuan Song, MD, PhD*, Jai Choi, MD†, Chandrakant Rao, MD*, Sagarika Nallu, MD‡, and Anthony D. Nicastri, MD* Primary vertebral Ewing sarcoma-primitive neuroectodermal tumor is uncommon. Although epidural extension has been seen in such tumors, cases with massive intraspinal involvement are decidedly rare. Here we present the case of a 4-year-old girl with back pain and difficulty walking. Magnetic resonance imaging showed a mass filling the spinal canal from T11 to the L3/L4 levels. Vertebral involvement with extension into the paraspinal soft tissue through neural foramina was seen. Histologically, a small-blue-cell tumor with strong membranous CD99 reactivity was noted. Molecular analysis revealed translocation t(11;22)(q24;q12), thus confirming the diagnosis of Ewing sarcoma-primitive neuroectodermal tumor. Our case emphasizes that vertebral Ewing sarcoma-primitive neuroectodermal tumor may present with massive intraspinal extension and should be included in the differential diagnosis of intraspinal lesions. © 2008 by Elsevier Inc. All rights reserved.
the bone, soft tissue, and nerve. They constitute the second most common malignant bone tumor in pediatric patients, usually involving long bones and pelvis. Primary vertebral Ewing sarcoma-peripheral primitive neuroectodermal tumor is uncommon [1], and a tumor with massive intraspinal extension is even less common. Case Report A 4-year-old girl presented with a 3-month history of limping after a fall, back pain, and progressive left lower extremity pain that later became bilateral. She developed constipation and difficulty urinating over a few days, and finally inability to stand up or walk. Thoracic and lumbar x-rays revealed mild scoliosis at the thoracolumbar junction, with convexity to the right and sclerosis of the L2 vertebral body. T1- and T2-weighted magnetic resonance imaging revealed a soft tissue mass filling the spinal canal starting at T11 and extending down to L3/L4 levels. The mass extended into the paraspinal soft tissue through neural foramina at L1-2 and L2-3 levels. Because of its size and extent, it was difficult to determine whether the mass was intradural or extradural. There was abnormal marrow signal at L1, L2, and L3 and involvement of the pedicle bilaterally at L1 and L2. The tumor demonstrated mostly homogeneous intermediate-to-low signal on T1-weighted images and heterogeneous high signal on T2-weighted images. Heterogeneous enhancement was noted on post-contrast images (Fig 1). At surgery, an epidural soft tissue mass was seen, and subtotal removal was performed. Histologically, the tumor consisted of sheets of small blue cells with hyperchromatic nuclei, scant cytoplasm, brisk mitotic figures (Fig 2), and infiltration of epidural fat. Immunohistochemically, the tumor cells showed strong membranous CD99 positivity. Intracellular glycogen was appreciated with focal strong staining for periodic acid Schiff that was digestible with diastase. Neuron-specific enolase was focally weakly positive. Reactivity was negative to CD56, S100, glial fibrillary acidic protein, neurofilament, synaptophysin, CD45 (leukocyte common antigen), muscle-specific actin, myoglobin, and myogenin. These findings were consistent with the diagnosis of Ewing sarcomaperipheral primitive neuroectodermal tumor. Further molecular analysis using reverse transcriptase-polymerase chain reaction revealed the translocation of t(11;22)(q24;q12) characteristic of Ewing sarcoma-peripheral primitive neuroectodermal tumor, and confirmed the diagnosis. The patient received combined radiotherapy and chemotherapy. At the time of this report, 22 months after surgery, the patient had no evidence of recurrence.
Song X, Choi J, Rao C, Nallu S, Nicastri AD. Primary Ewing sarcoma of lumbar spine with massive intraspinal extension. Pediatr Neurol 2008;38:58-60.
Discussion
Introduction
Ewing sarcoma and peripheral primitive neuroectodermal tumor, rare sarcomas of bone and soft tissue, were initially regarded as separate entities [2]. However, both tumors are composed of undifferentiated small, round blue cells, and almost 100% of Ewing sarcoma and peripheral primitive neuroectodermal tu-
Ewing sarcoma and peripheral primitive neuroectodermal tumor comprise a group of small-round-cell tumors of
From Departments of *Pathology, †Radiology, and ‡Neurology, SUNY Downstate Medical Center, Brooklyn, New York.
58
PEDIATRIC NEUROLOGY
Vol. 38 No. 1
Communications should be addressed to: Dr. Rao; Department of Pathology; SUNY Downstate Medical Center; 450 Clarkson Ave, Box 25; Brooklyn, NY 11203. E-mail: [email protected] Received June 21, 2007; accepted September 5, 2007.
© 2008 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2007.09.003 ● 0887-8994/08/$—see front matter
and peripheral primitive neuroectodermal tumor are now almost universally regarded as a common histologic spectrum of the Ewing family of tumors. Primary skeletal Ewing sarcoma-peripheral primitive neuroectodermal tumor usually arises in long bones and pelvis. Primary vertebral origin is uncommon, reportedly 3.5-9.8% [4], and mostly in the lumbosacral region. The tumors usually extend beyond the affected vertebral body into the posterior spinal elements and paraspinal soft tissues. Fewer than 10 cases of epidural extension have been clearly documented [4-10]; in one series, however, epidural extension was thought to be a common feature, with 91% of 51 cases showing this characteristic [4]. Although epidural invasion may involve several vertebral levels, the extensive intraspinal involvement seen in the present case is decidedly rare. Intradural invasions have not been reported in skeletal Ewing sarcoma-peripheral primitive neuroectodermal tumor cases. They are, however, seen in extraskeletal Ewing sarcoma-peripheral primitive neuroectodermal tumor cases. Extraskeletal Ewing sarcoma-peripheral primitive neuroectodermal tumor has similar histology to skeletal Ewing sarcoma-peripheral primitive neuroectodermal tumor. The extraskeletal variant most commonly affects the chest wall and paravertebral extradural locations. A literature review reveals 42 extraskeletal Ewing sarcoma-peripheral primitive neuroectodermal tumor cases with epidural involvement [1,2,11-12]. Additionally, 14 intradural and extramedullary cases have been reported [12]. These tumors follow an aggressive course, with a high recurrence rate and rapid progress and with metastases most commonly to lung, bone, and bone marrow. Definitive diagnosis of Ewing sarcoma-peripheral primitive neuroectodermal tumor relies on pathological assessment. Light microscopy reveals a predominantly undifferentiated small-blue-cell tumor. Neuronal differentiation and intracytoplasmic glycogen may be present. Distinct membra-
Figure 1. Spinal magnetic resonance imaging. (A) Sagittal post-contrast T1-weighted image (TR/TE ⫽ 444/10.5 ms) reveals abnormal marrow signal including L1-L3 vertebral bodies, and a soft tissue mass filling the spinal canal. (B) Axial T2-weighted image (TR/TE ⫽ 2500/ 129.8 ms) at the level of L2/3 disc space reveals tumor extension through the neural foramina.
mor are reactive with antibodies to CD99 (p30/32 MIC2), a cell-surface glycoprotein. Recently, it was established that more than 80% cases of both Ewing sarcoma and peripheral primitive neuroectodermal tumor share a specific t(11;22)(q24;q12) balanced translocation [3]; consequently, a chimeric protein EWS/ FLI-1 is expressed by the tumor. Thus, Ewing sarcoma
Figure 2. Photomicrograph of tumor tissue reveals diffuse proliferation of small blue cells with hyperchromatic nuclei, scant cytoplasm, and brisk mitosis (hematoxylin and eosin stain, original magnification ⫻ 100). Tumor cells showed strong membranous CD99 positivity (not shown).
Song et al: ES-PPNET With Intraspinal Extension 59
nous CD99 expression is characteristic and a highly reliable positive marker for Ewing sarcoma-peripheral primitive neuroectodermal tumor, but is not specific [3,12]. Demonstration of the translocation t(11;22)(q24;q12) with either molecular or cytogenetic analysis has been recognized as the diagnostic gold standard. Other poorly differentiated small-round-blue-cell tumors (including neuroblastoma, lymphoma, and rhabdomyosarcoma) should be included in the differential diagnosis. Immunohistochemically, neuroblastoma would be positive for CD56, muscle marker positivity would support a diagnosis of rhabdomyosarcoma, and a monoclonal lymphoid population with immunohistochemistry studies would support the diagnosis of lymphoma. Findings on magnetic resonance imaging were nonspecific. Some of the neuroradiological features seen in this patient are shared by myxopapillary ependymoma, such as isointensity on T1-weighted images, slight hyperintensity on T2-weighted images, well-defined borders with contrast enhancement [6], and typical extension for several vertebral levels [13,14]. Thus, myxopapillary ependymoma, although uncommon in the pediatric population (8-20% in the first two decades), with rare neural foramina extension and bony invasion, can be considered in the differential diagnosis [14]. Histologically, ependymal true rosettes or pseudorosettes and a papillary arrangement of cuboidal or columnar tumor cells are characteristic of myxopapillary ependymoma, a pattern distinct from Ewing sarcoma-peripheral primitive neuroectodermal tumor. Surgical decompression is needed for neurologically unstable patients. Adjuvant treatments with radiotherapy and vincristine-doxorubicin-cyclophosphamidebased multiagent chemotherapy with or without actinomycin should follow, to minimize the risk of local recurrence [15]. The overall 5-year survival rate is approximately 49-60% [4,15]. New and evolving techniques include immunotherapeutic approaches targeting the translocation cell markers, as well as high-dose chemotherapy [9]. The latter has shown a significant survival advantage in nonmetastatic disease.
60
PEDIATRIC NEUROLOGY
Vol. 38 No. 1
We thank Ethan Benardete, MD, PhD, for his helpful input in case discussion and Lynette G. Sheffield, PhD, for manuscript review.
References [1] Harimaya K, Oda Y, Matsuda S, Tanaka K, Chuman H, Iwamoto Y. Primitive neuroectodermal tumor and extraskeletal Ewing sarcoma arising primarily around the spinal column: report of four cases and a review of the literature. Spine 2003;28:E408-12. [2] Angervall L, Enzinger FM. Extraskeletal neoplasm resembling Ewing’s sarcoma. Cancer 1975;36:240-51. [3] Folpe AL, Goldblum JR, Rubin BP, et al. Morphologic and immunophenotypic diversity in Ewing family tumors: a study of 66 genetically confirmed cases. Am J Surg Pathol 2005;29:1025-33. [4] Ilaslan H, Sundaram M, Unni KK, Dekutoski MB. Primary Ewing’s sarcoma of the vertebral column. Skeletal Radiol 2004;33: 506-13. [5] Anderson FM, Carson MJ. Spinal cord tumors in children: a review of the subject and presentation of twenty-one cases. J Pediatr 1953;43:190-207. [6] Bemporad JA, Sze G, Chaloupka JC, Duncan C. Pseudohemangioma of the vertebra: an unusual radiographic manifestation of primary Ewing’s sarcoma. AJNR Am J Neuroradiol 1999;20:1809-13. [7] Hashimoto M, Akabane Y, Tate E. Ewing’s sarcoma of the sacrum. Radiat Med 1999;17:451-3. [8] Lam CH, Nagib MG. Nonteratomatous tumors in the pediatric sacral region. Spine 2002;27:E284-7. [9] Ricchetti ET, Erol B, Stern J, Russo P, States L, Dormans JP. Lower back pain and mass in a 13-year-old girl. Clin Orthop Relat Res 2005;430:248-57. [10] Siami-Namini K, Shuey-Drake R, Wilson D, Francel P, Perry A, Fung KM. A 15-year-old female with progressive myelopathy. Brain Pathol 2005;15:265-7. [11] Scheithauer BW, Egbert BM. Ewing’s sarcoma of the spinal epidural space: report of two cases. J Neurol Neurosurg Psychiatry 1978;41:1031-5. [12] Mobley BC, Roulston D, Shah GV, Bijwaard KE, McKeever PE. Peripheral primitive neuroectodermal tumor/Ewing’s sarcoma of the craniospinal vault: case reports and review. Hum Pathol 2006;37:845-53. [13] Schuurmans M, Vanneste JA, Verstegen MJ, van Furth WR. Spinal extramedullary anaplastic ependymoma with spinal and intracranial metastases. J Neurooncol 2006;79:57-9. [14] Fassett DR, Pingree J, Kestle JR. The high incidence of tumor dissemination in myxopapillary ependymoma in pediatric patients: report of five cases and review of the literature. J Neurosurg 2005;102(1 Suppl):59-64. [15] Marco RA, Gentry JB, Rhines LD, et al. Ewing’s sarcoma of the mobile spine. Spine 2005;30:769-73.
the bone, soft tissue, and nerve. They constitute the second most common malignant bone tumor in pediatric patients, usually involving long bones and pelvis. Primary vertebral Ewing sarcoma-peripheral primitive neuroectodermal tumor is uncommon [1], and a tumor with massive intraspinal extension is even less common. Case Report A 4-year-old girl presented with a 3-month history of limping after a fall, back pain, and progressive left lower extremity pain that later became bilateral. She developed constipation and difficulty urinating over a few days, and finally inability to stand up or walk. Thoracic and lumbar x-rays revealed mild scoliosis at the thoracolumbar junction, with convexity to the right and sclerosis of the L2 vertebral body. T1- and T2-weighted magnetic resonance imaging revealed a soft tissue mass filling the spinal canal starting at T11 and extending down to L3/L4 levels. The mass extended into the paraspinal soft tissue through neural foramina at L1-2 and L2-3 levels. Because of its size and extent, it was difficult to determine whether the mass was intradural or extradural. There was abnormal marrow signal at L1, L2, and L3 and involvement of the pedicle bilaterally at L1 and L2. The tumor demonstrated mostly homogeneous intermediate-to-low signal on T1-weighted images and heterogeneous high signal on T2-weighted images. Heterogeneous enhancement was noted on post-contrast images (Fig 1). At surgery, an epidural soft tissue mass was seen, and subtotal removal was performed. Histologically, the tumor consisted of sheets of small blue cells with hyperchromatic nuclei, scant cytoplasm, brisk mitotic figures (Fig 2), and infiltration of epidural fat. Immunohistochemically, the tumor cells showed strong membranous CD99 positivity. Intracellular glycogen was appreciated with focal strong staining for periodic acid Schiff that was digestible with diastase. Neuron-specific enolase was focally weakly positive. Reactivity was negative to CD56, S100, glial fibrillary acidic protein, neurofilament, synaptophysin, CD45 (leukocyte common antigen), muscle-specific actin, myoglobin, and myogenin. These findings were consistent with the diagnosis of Ewing sarcomaperipheral primitive neuroectodermal tumor. Further molecular analysis using reverse transcriptase-polymerase chain reaction revealed the translocation of t(11;22)(q24;q12) characteristic of Ewing sarcoma-peripheral primitive neuroectodermal tumor, and confirmed the diagnosis. The patient received combined radiotherapy and chemotherapy. At the time of this report, 22 months after surgery, the patient had no evidence of recurrence.
Song X, Choi J, Rao C, Nallu S, Nicastri AD. Primary Ewing sarcoma of lumbar spine with massive intraspinal extension. Pediatr Neurol 2008;38:58-60.
Discussion
Introduction
Ewing sarcoma and peripheral primitive neuroectodermal tumor, rare sarcomas of bone and soft tissue, were initially regarded as separate entities [2]. However, both tumors are composed of undifferentiated small, round blue cells, and almost 100% of Ewing sarcoma and peripheral primitive neuroectodermal tu-
Ewing sarcoma and peripheral primitive neuroectodermal tumor comprise a group of small-round-cell tumors of
From Departments of *Pathology, †Radiology, and ‡Neurology, SUNY Downstate Medical Center, Brooklyn, New York.
58
PEDIATRIC NEUROLOGY
Vol. 38 No. 1
Communications should be addressed to: Dr. Rao; Department of Pathology; SUNY Downstate Medical Center; 450 Clarkson Ave, Box 25; Brooklyn, NY 11203. E-mail: [email protected] Received June 21, 2007; accepted September 5, 2007.
© 2008 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2007.09.003 ● 0887-8994/08/$—see front matter
and peripheral primitive neuroectodermal tumor are now almost universally regarded as a common histologic spectrum of the Ewing family of tumors. Primary skeletal Ewing sarcoma-peripheral primitive neuroectodermal tumor usually arises in long bones and pelvis. Primary vertebral origin is uncommon, reportedly 3.5-9.8% [4], and mostly in the lumbosacral region. The tumors usually extend beyond the affected vertebral body into the posterior spinal elements and paraspinal soft tissues. Fewer than 10 cases of epidural extension have been clearly documented [4-10]; in one series, however, epidural extension was thought to be a common feature, with 91% of 51 cases showing this characteristic [4]. Although epidural invasion may involve several vertebral levels, the extensive intraspinal involvement seen in the present case is decidedly rare. Intradural invasions have not been reported in skeletal Ewing sarcoma-peripheral primitive neuroectodermal tumor cases. They are, however, seen in extraskeletal Ewing sarcoma-peripheral primitive neuroectodermal tumor cases. Extraskeletal Ewing sarcoma-peripheral primitive neuroectodermal tumor has similar histology to skeletal Ewing sarcoma-peripheral primitive neuroectodermal tumor. The extraskeletal variant most commonly affects the chest wall and paravertebral extradural locations. A literature review reveals 42 extraskeletal Ewing sarcoma-peripheral primitive neuroectodermal tumor cases with epidural involvement [1,2,11-12]. Additionally, 14 intradural and extramedullary cases have been reported [12]. These tumors follow an aggressive course, with a high recurrence rate and rapid progress and with metastases most commonly to lung, bone, and bone marrow. Definitive diagnosis of Ewing sarcoma-peripheral primitive neuroectodermal tumor relies on pathological assessment. Light microscopy reveals a predominantly undifferentiated small-blue-cell tumor. Neuronal differentiation and intracytoplasmic glycogen may be present. Distinct membra-
Figure 1. Spinal magnetic resonance imaging. (A) Sagittal post-contrast T1-weighted image (TR/TE ⫽ 444/10.5 ms) reveals abnormal marrow signal including L1-L3 vertebral bodies, and a soft tissue mass filling the spinal canal. (B) Axial T2-weighted image (TR/TE ⫽ 2500/ 129.8 ms) at the level of L2/3 disc space reveals tumor extension through the neural foramina.
mor are reactive with antibodies to CD99 (p30/32 MIC2), a cell-surface glycoprotein. Recently, it was established that more than 80% cases of both Ewing sarcoma and peripheral primitive neuroectodermal tumor share a specific t(11;22)(q24;q12) balanced translocation [3]; consequently, a chimeric protein EWS/ FLI-1 is expressed by the tumor. Thus, Ewing sarcoma
Figure 2. Photomicrograph of tumor tissue reveals diffuse proliferation of small blue cells with hyperchromatic nuclei, scant cytoplasm, and brisk mitosis (hematoxylin and eosin stain, original magnification ⫻ 100). Tumor cells showed strong membranous CD99 positivity (not shown).
Song et al: ES-PPNET With Intraspinal Extension 59
nous CD99 expression is characteristic and a highly reliable positive marker for Ewing sarcoma-peripheral primitive neuroectodermal tumor, but is not specific [3,12]. Demonstration of the translocation t(11;22)(q24;q12) with either molecular or cytogenetic analysis has been recognized as the diagnostic gold standard. Other poorly differentiated small-round-blue-cell tumors (including neuroblastoma, lymphoma, and rhabdomyosarcoma) should be included in the differential diagnosis. Immunohistochemically, neuroblastoma would be positive for CD56, muscle marker positivity would support a diagnosis of rhabdomyosarcoma, and a monoclonal lymphoid population with immunohistochemistry studies would support the diagnosis of lymphoma. Findings on magnetic resonance imaging were nonspecific. Some of the neuroradiological features seen in this patient are shared by myxopapillary ependymoma, such as isointensity on T1-weighted images, slight hyperintensity on T2-weighted images, well-defined borders with contrast enhancement [6], and typical extension for several vertebral levels [13,14]. Thus, myxopapillary ependymoma, although uncommon in the pediatric population (8-20% in the first two decades), with rare neural foramina extension and bony invasion, can be considered in the differential diagnosis [14]. Histologically, ependymal true rosettes or pseudorosettes and a papillary arrangement of cuboidal or columnar tumor cells are characteristic of myxopapillary ependymoma, a pattern distinct from Ewing sarcoma-peripheral primitive neuroectodermal tumor. Surgical decompression is needed for neurologically unstable patients. Adjuvant treatments with radiotherapy and vincristine-doxorubicin-cyclophosphamidebased multiagent chemotherapy with or without actinomycin should follow, to minimize the risk of local recurrence [15]. The overall 5-year survival rate is approximately 49-60% [4,15]. New and evolving techniques include immunotherapeutic approaches targeting the translocation cell markers, as well as high-dose chemotherapy [9]. The latter has shown a significant survival advantage in nonmetastatic disease.
60
PEDIATRIC NEUROLOGY
Vol. 38 No. 1
We thank Ethan Benardete, MD, PhD, for his helpful input in case discussion and Lynette G. Sheffield, PhD, for manuscript review.
References [1] Harimaya K, Oda Y, Matsuda S, Tanaka K, Chuman H, Iwamoto Y. Primitive neuroectodermal tumor and extraskeletal Ewing sarcoma arising primarily around the spinal column: report of four cases and a review of the literature. Spine 2003;28:E408-12. [2] Angervall L, Enzinger FM. Extraskeletal neoplasm resembling Ewing’s sarcoma. Cancer 1975;36:240-51. [3] Folpe AL, Goldblum JR, Rubin BP, et al. Morphologic and immunophenotypic diversity in Ewing family tumors: a study of 66 genetically confirmed cases. Am J Surg Pathol 2005;29:1025-33. [4] Ilaslan H, Sundaram M, Unni KK, Dekutoski MB. Primary Ewing’s sarcoma of the vertebral column. Skeletal Radiol 2004;33: 506-13. [5] Anderson FM, Carson MJ. Spinal cord tumors in children: a review of the subject and presentation of twenty-one cases. J Pediatr 1953;43:190-207. [6] Bemporad JA, Sze G, Chaloupka JC, Duncan C. Pseudohemangioma of the vertebra: an unusual radiographic manifestation of primary Ewing’s sarcoma. AJNR Am J Neuroradiol 1999;20:1809-13. [7] Hashimoto M, Akabane Y, Tate E. Ewing’s sarcoma of the sacrum. Radiat Med 1999;17:451-3. [8] Lam CH, Nagib MG. Nonteratomatous tumors in the pediatric sacral region. Spine 2002;27:E284-7. [9] Ricchetti ET, Erol B, Stern J, Russo P, States L, Dormans JP. Lower back pain and mass in a 13-year-old girl. Clin Orthop Relat Res 2005;430:248-57. [10] Siami-Namini K, Shuey-Drake R, Wilson D, Francel P, Perry A, Fung KM. A 15-year-old female with progressive myelopathy. Brain Pathol 2005;15:265-7. [11] Scheithauer BW, Egbert BM. Ewing’s sarcoma of the spinal epidural space: report of two cases. J Neurol Neurosurg Psychiatry 1978;41:1031-5. [12] Mobley BC, Roulston D, Shah GV, Bijwaard KE, McKeever PE. Peripheral primitive neuroectodermal tumor/Ewing’s sarcoma of the craniospinal vault: case reports and review. Hum Pathol 2006;37:845-53. [13] Schuurmans M, Vanneste JA, Verstegen MJ, van Furth WR. Spinal extramedullary anaplastic ependymoma with spinal and intracranial metastases. J Neurooncol 2006;79:57-9. [14] Fassett DR, Pingree J, Kestle JR. The high incidence of tumor dissemination in myxopapillary ependymoma in pediatric patients: report of five cases and review of the literature. J Neurosurg 2005;102(1 Suppl):59-64. [15] Marco RA, Gentry JB, Rhines LD, et al. Ewing’s sarcoma of the mobile spine. Spine 2005;30:769-73.